2-(n-cycloalkyl-phenylamino)-2-imidazolines-(2) and salts thereof

ABSTRACT

COMPOUND OF THE FORMULA   2-((CYCLOPENTYL)-N(-Y)-)-2-IMIDAZOLINE, OR 2-((CYCLO-   HEPTYL)-N(-Z)-)-2-IMIDAZOLINE   WHEREIN 1 IS 2,6-DICHLORO-PHENYL, 2-CHLORO-L-METHY6-PHENYL, 2CHLORO-4-METHYL-PHENYL, 2-METHYL-4-CHLORO-PHENYL,2CHLORO-PHENYL, 2,4-DICHLORO-PHENYL, 2-METHYL-PHENYL. 2,6-DIETHYL-PHENYL, 4-BROMO-PHENYL, 2,6- DICHLORO-4BROMO-PHENYL, 4-CYANO-PHENYL, 4-FLUORO-PHENYL OR 2-TRI FLUOROMETHYL-PHENYL, 2-METHOXY-4-CHLORO-PHENYL OR 2CHLORO-3-METHYL-PHENYL, AND Z IS   (2-CL,6-R7-PHENYL)-   WHERE R7 IS CHLORINE OR METHYL, AND THEIR NON-TOXIC, PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS, THE COMPOUNDS AS WELL AS THEIR SALTS ARE USEFUL AS ANALGESICS.

United States Patent W 3,740,401 2-(N-CYCLOALKYL-PHENYLAMINO)-2-IMIDAZO-LINES-(2) AND SALTS THEREOF Helmut Stahle, Herbert Koppe, Werner Kummer,and

Klaus Stockhaus, Ingelheim am Rhein, Germany, assignors to BoehringerIngelheim G.m.b.H., Ingelheim am Rhein, Germany No Drawing. Filed Nov.18, 1970, Ser. No. 90,845 Claims priority, application Germany, Nov. 19,1969, P 10 58 212.8 Int. Cl. 007d 49/34, 57/48 US. Cl. 260254 19 ClaimsABSTRACT OF THE DISCLOSURE Compounds of the formula Y is2,6-dichloro-phenyl, 2-chloro-6-methyl-phenyl, 2- chloro-4methyl-phenyl, 2-methyl-4-chloro-phenyl, 2- chloro-phenyl,2,4-dichloro-phenyl, Z-methyl-phenyl, 2,6-diethy1-phenyl,4-bromo-pheny1, 2,6-dichloro-4- bromo-phenyl, 4-cyan0-phenyl,4-fluoro-phenyl, 2-trifluoromethyl-phenyl, 2-rnethoxy-4-chloro-phenyl or2- chloro-3-methyl-phenyl, and

Zis

where R is chlorine or methyl,

and their non-toxic, pharmacologically acceptable acid addition salts;the compounds as well as their salts are useful as analgesics.

This invention relates to novelZ-(N-cycloalkylphenylamino)-2-imidazolines and non-toxic acid additionsalts thereof, as well as to a method of preparing these compounds.

More particularly, the present invention relates to a novel class of2-(N-cycloalkyl-phenylamino)-2-imidazolines of the formula V N-CH l l H:0 CH;

Patented June 19, 1973 Y is 2,6-dichloropheny1,2-chloro-6-methyl-phenyl, 2-

chloro 4 methyl-phenyl, 2-rnethyl-4-chloro-phenyl, 2-chloro-phenyl,2,4-dichlorophenyl, Z-methyl-phenyl, 2,6 diethyl-phenyl, 4 bromo-phenyl,2,6-dichloro-4- brorno-phenyl, 4 cyano-phenyl, 4-fluoro-phenyl,2-trifluoromethyl-phenyl, 2-methoXy-4-chlor0-phenyl or 2-chloro-3-methyl-phenyl, and

Z is

where R, is chlorine or methyl,

and their non-toxic, pharmacologically acceptable acid addition salts.

Especially preferred are compounds of the formula wherein R is chlorineor methyl, and n is 1 or 3,

CHzCHz (III) wherein X is a halogen atom, preferably chlorine or bromineand n has the same meaning as in Formula Ib.

The reaction is advantageously carried out by heating the reactants inthe presence of an organic solvent and an acid binding agent to elevatedtemperatures, preferably to about 45 C. and the boiling temperature ofthe reaction mixture. The most advantageous specific reaction conditionsdepend largely upon the reactivity of the individual reactants and aremost advantageously determined by preliminary tests.

The alkylation takes place exclusively at the nitrogen bridge atom,which can be proven by means of NMR spectroscopy; in case ofsubstitution at the nitrogen bridge atom the methylene protons of theimidazoline ring appear as a singulet at about 6 p.p.m. r-scale).

The 2-(N-cycloalkyl-phenylamino)-2-imidazolines defined by Formula I arebases and therefore form acid addition salts with inorganic and organicacids. Such addition salts may be prepared in conventional manner, thatis, for example, by dissolving the free bases in a solvent andacidifying the solution with the desired acid. Examples of non-toxic,pharmacologically acceptable acid addition salts are those formed withhydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid,sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionicacid, butyric acid, oxalic acid, valeric acid, capronic acid, malonicacid, succinic acid, glutaric acid, maleic acid, fumaric acid, lacticacid, tartaric acid, citric acid, malic acid, benzoic acid,p-hydroxybenzoic acid, phthalic acid, cinnamic acid, salicylic acid,ascorbic acid, 8-chlorotheophylline or the like.

The following examples further illustrate the present invention and willenable others skilled in the art to understand it more completely. Itshoud be understood, however that the invention is not limited solely tothe particular examples given below.

EXAMPLE 1 2- [N- 2,6 -dichlorophenyl) -N- (cyclop entyl) -amino]Z-imidazoline (a) 46 g. (0.2 mol) of 2-(2,fi-dichlorophenylamino) 2-imidazoline are refluxed with 44.6 g. (150%) of bromocyclopentane and23.2 g. (110%) of sodium carbonate in 100 ml. of n-butanol for 8 hours.Hereupon, inorganic salts are filtered off and the filtrate isevaporated to dryness in vacuo. The residue is dissolved in dilutedhydrochloric acid and the solution is adjusted to pH 7 with 2 N sodiumhydroxide solution. At this pH-value it is extracted several times withether and the ether extracts, containing unreacted starting imidazoline,are discarded. After complete separation of the starting imidazoline,the aqueous solution is alkalized, after treatment with active char coalwith N sodium hydroxide solution. The new imidazoline base separatingcrystalline is sucked off, washed with water and dried. Thus, there isobtained thin-layer chromatographically uniform 2-[N-(2,6-dichlorophenyl)- N-(cyclopentyl)-amino] 2 imidazoline of M.P.12l- 123 C. Yield: 33.0 g. (corresponds to 55.5% of theory).

(b) 6.9 g. (0.03 mol) of 2-(2,6-dichlorophenylamino)- Z-imidazoh'ne aredissolved together with 7.35 g. (150%) of bromocyclopentane in ml. ofabsolute methanol and the reaction mixture in a bomb tube is heated for16 hours on the boiling water bath.

After this time, excess starting material and solvent is evaporated invacuo and the remaining residue is dissolved in diluted hydrochloricacid. By means of fractionated ether extraction at various pH-values thenovel imidazoline is separated from the starting imidazoline (proof bythin-layer chromatography).

The ether extracts containing the cyclopentyl-imidazoline base areunited, dried over drierite and evaporated in vacuo. There remain 1.3 g.of 2[N-(2,6-dichlorophenyl)-N-cyclopentyl-amino]-2-imidazolinc of M.P.121- 123 C.

Analogous to Example 1, the following compounds, listed in the table,may be synthetized:

Compounds represented by formula:

/NCH;

NC R 33-11 ICH Ra 1!: H 0 OH,

Yield (in percent Example M.P. of N o. 1 R2 R; n (1n C.) theory) 6-CH3 H1 -102 42. 0 4-CH H 1 116-117 36. 1 2-CH H 1 102-104 45. 5 H H 1 103-10541. 7 4-01 H 1 124-125 24. 6 G-Cl H 3 1 210-213 20. 6 H H 1 79-81 41. 16-CH3 H 3 -197 16. 2 6-C H H 1 Oil 23. 4 H H 1 133-134 27. 4 i-Br 6-C1 1112-118 35. 4 H H 1 132-135 22. 5 H H 1 107-110 43. 6 H H 1 103-105 45.6 l-Cl H 1 101-104 37. 7 3-CH3 H 1 126-127 61. 8

1 Nitrate.

The compounds according to the present invention, that is, thoserepresented by Formula I above and their nontoxic, pharmacologicallyacceptable acid addition salts have useful pharmacodynamic properties.More particularly, the compounds of the instant invention exhibitanalgesic activities in warm-blooded animals, such as mice and rats.

For pharmaceutical purposes the compounds according to the presentinvention are administered to warm-blooded animals perorally, enterallyof parenterally, preferably perorally, as active ingredients incustomary dosage unit compositions, that is, those consistingessentially of an inert pharmaceutical carrier and one eifective dosageunit of the active ingredient, such as tablets, coated pills, capsules,waters, powders, solutions, suspensions, emulsions, syrups,suppositories and the like. One eifective oral dosage unit of thecompounds according to the invention is from 0.0084 to 1.66 mgm./kg.body weight, preferably 0.084 to 0.42 mgm./kg. body Weight.

The following examples illustrate a few dosage unit compositionscomprising a compound of the present invention as an active ingredientand represent the best mode contemplated of putting the invention intopractical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 18 Coated tablets The tablet composition was compounded form thefollowing ingredients:

phosphate and the silicic acid, the mixture is thoroughly kneaded withan aqueous 10% solution of the soluble starch, and the resultant moistmass is granulated through a 1.5 mm.-mesh screen and dried. Thegranulates is admixed with the magnesium stearate, and the resultingEXAMPLE 19 Hypodermic solution The solution is compounded from thefollowing ingredients:

Parts 2 [N (2-chloro-6-methylphenyl)-N-cyclohexyl)- amino]-2-imidazoline5.0 Sodium chloride 18.

Distilled water s.q. ad. 2000 parts by vol.

Preparation: The imidazoline compound and the sodium chloride aredissolved in a suflicient amount of distilled Water, the solution isdiluted to the indicated volume with additional distilled water,filtered until free from suspended matter, and the filtrate is filledinto 2 ml.-ampules in an atmosphere of nitrogen. The filled ampules arethen sealed and sterilized for 20 minutes at 120 C. Each ampule contains5 mgm. of the imidazoline compound. When the contents thereof wereadministered intramusculary to a warm-blooded animal of about 60 kg.body Weight in need of such treatment, very effective analgesic actionwas produced.

EXAMPLE 20 Rectal suppositories The suppository composition iscompounded from the following ingredients:

Cocoa butter q.s. ad. 1700.

The cocoa butter is melted, the active ingredient and the lactose areadded, the mixture is allowed to cool slightly and is then homogenized.Thereafter, the composition is poured into cold suppository moldsholding 1700 mgm. each. Every individual suppository contains 3 mgm. ofthe imidazoline compound.

When administered rectally to a warm-blooded animal of about 60 kg. bodyweight in need of such treatment, very effective analgesic action wasproduced.

Analogous results were obtained when any one of the other imidazolinecompounds embraced by Formula I or a non-toxic acid addition saltthereof was substituted for the particular imidazoline derivative inExamples 18 through 20. Likewise, the amount of active ingredient inthese illustrative examples may be varied to achieve the dosage unitrange set forth above, and the amounts and nature of the inertpharmaceutical carrier ingredients may be varied to meet particularrequirements.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily apparent to othersskilled in the art that the invention is not limited to those particularembodiments and that various changes and modifications may be madewithout departing from the spirit of the invention or the scope of theappending claims.

We claim: 1. A compound of the formula /NCH3 Y-N-G /H N-CHa o H H20 0H2HzC Hz Y is 2,6-dichloro-phenyl, 2-chloro-6-methyl-phenyl, 2-

chloro 4 methyl-phenyl, 2-methyl-4-chloro-phenyl, 2-chloro-phenyl,2,4-dichloro-phenyl, Z-methyl-phenyl, 2, 6 diethyl-phenyl,4-bromo-phenyl, 2,'6-dichloro-4- bromo-phenyl, 4-cyano-phenyl,4fluoro-phenyl, Z-trifluoromethyl-phenyl, 2-methoXy-4-chloro-phenyl or2- chloro-3-methyl-phenyl, and

Z is

where R is chlorine or methyl, or a non-toxic, pharmacologicallyacceptable acid addition salt thereof.

2. A compound of the formula Q K l (L H N-OH: R5 H HEC/ CHz H2( Z)nwhere R7 is chlorine or methyl,

wherein R is chlorine or methyl, and

n is an integer of 1 or 3 or a non-toxic, pharmacologocially acceptableacid addiaddition sale thereof.

3. A compound according to claim 2 which is 2-[N- (2,6-dichlorophenyl) N(cyclopentyl)-amino]-2-imidazoline or a non-toxic, pharmacologicallyacceptable acid addition salt thereof.

4. A compound according to claim 2 which is 2-[N- (2-chloro 6methylphenyl)-N-(cyclopentyl)-amino]- 2-imidazoline or a non-toxic,pharmacologically acceptable acid addition salt thereof.

5. A compound according to claim 2 which is 2-[N (2,6-dichlorophenyl) N(cycloheptyl)-amino]-2-imidazoline or a non-toxic, pharmacologicallyacceptable acid addition salt thereof.

6. A compound according to claim 2 which is 2-[N- (Z-chloro 6methylphenyl)-N-(cyclohepty1)-amino]- Z-imidazoline or a non-toxic,pharmacologically accept able acid addition salt thereof.

7. A compound according to claim 1 which is 2-[N- (2-chloro 4methylphenyl)-N-(cyclopentyl)-amino]- Z-imidazoline or a non-toxic,pharmacologically acceptable acid addition salt thereof.

8. A compound according to claim 1 which is 2-[N- (Z-methyl 4chloro-pheny1)-N-(cyclopentyl)-amino]- Z-imidazoline or a non-toxic,pharmacologically acceptable acid addition salt thereof.

9. A compound according to claim 1 which is 2-[N- (2-chlorophenyl) N(cyclopentyl)-amino]-2-imidazoline or a non-toxic, pharmacologicallyacceptable acid addition salt thereof.

10. A compound according to claim 1 which is 2-[N- (2,4-dichloropheny1)N (cyclopentyl)amino]-2-imid- 7 azoline or a non-toxic,pharmacologically acceptable acid addition salt thereof.

11. A compound according to claim 1 which is 2-[N- (Z-methylphenyl) N(cyclopentyl)-amino]-2-imidazoline or a non-toxic, pharmacologicallyacceptable acid addition salt thereof.

12. A compound according to claim 1 which is 2-[N- (2,6-diethylphenyl) N(cyclopentyD-amino]-2-imidazoline or a non-toxic, pharmacologicallyacceptable acid addition salt thereof.

13. A compound according to claim 1 which is 2-[N- (4-b1'omopheny1) N(cyclopentyl)-amino]-2-imidazoline or a non-toxic, pharmacologicallyacceptable acid addition salt thereof.

14. A compound according to claim 1 which is 2-[N- (2,6dichloro-4bromo-phenyl) N (cyclopentyl)- amino]-2- imidazoline or anon-toxic, pharmacologically acceptable acid addition salt thereof.

15. A compound according to claim 1 which is 2-[N- (4-cyanophenyl) N(cyclopentyl)-amino]-2-imidazoline or-a non-toxic, pharmacologicallyacceptable acid addition salt thereof.

16. A compound according to claim 1 which is 2-[N- (4-fiuorophenyl) N(cyclopentyl)-amino]-2-imidazoline or a non-toxic, pharmacologicallyacceptable acid addition salt thereof.

17. A compound according to claim 1 which is 2-[N-(Z-trifiuoro-methylphenyl) N (cyclopentyl)-amino]- Z-imidazoline or anon-toxic, pharmacologically acceptable acid addition salt thereof.

18. A compound according to claim 1 which is 2-[N-(Z-methoxy-4-ch1orophenyl) N (cyclopentyl)-amino]- References CitedUNITED STATES PATENTS 2,899,426 8/1959 Bloom 260-309.6

3,146,240 8/1964 Hageman et a1. 260--309.6

FOREIGN PATENTS 623,305 4/1963 Belgium 260309.6

539,179 11/1931 Germany 260-3096 1,016,514 1/1966 Great Britain 260309.6

OTHER REFERENCES Urech et al.: Helv. Chim. Acta, Vol. 33, pp. 1386-1407(1950).

Urech et al.: Chem. Abst., vol. 45, columns 2478-9 (1951).

Tronche et al.: Chem. Abst., vol. 55, column 11396 (1961). Aspinall: J.Amer. Chem. Soc., vol. 73, 602-3 (1951).

NATALIE TROUSOF, Primary Examiner US. Cl. X.R.

